This proposal describes a 5-year plan to develop an independent clinician-scientist focused on the pharmacological manipulation of cancer cell metabolism to improve therapeutic responses. This project will be co-mentored by Dr. Craig Thompson, Director, Abramson Cancer Center, and Dr. Peter O'Dwyer, Director, Developmental Therapeutics at the University of Pennsylvania. Both mentors have an established record of successfully mentoring clinician-scientists to highly productive research careers in oncology. This award will allow Dr. Amaravadi to obtain didactic training in biostatistics, molecular techniques, and pharmacokinetic modeling. It will also provide protected time for mentored training that will enable the candidate to conduct a series of clinical trials and laboratory investigations. These studies are designed to elucidate the role of targetable components of cancer cell metabolism as critical determinants of therapeutic outcomes. An important problem for cancer care is that therapies developed on the basis of their ability to induce apoptosis are often ineffective for malignancies with defective apoptosis. Two non-apoptotic responses to cancer therapy are necrosis and autophagy. The fundamental characteristics of cancer cell metabolism provide the basis for why cancer cells preferentially undergo these processes in response to systemic therapy. This project is designed to establish the clinical significance of necrosis and autophagy in patients undergoing therapy through the completion of two specific aims 1) To correlate measurements of necrosis, apoptosis and autophagy to clinical outcomes in patients undergoing cancer therapy, and 2) To determine the antitumor activity of chloroquine as an inhibitor of autophagy. The first specific aim will be addressed by applying a serum ELISA, immunohistochemical, and EM methods to blood and tissue samples from patients enrolled on clinical trials for advanced melanoma. The second aim will be the completion of the preclinical evaluation of hydroxychloroquine using xenograft tumor models followed by Phase I and Phase II clinical trials of hydroxychloroquine in patients with refractory malignancies. Multidisciplinary training during this award will allow Dr. Amaravadi to independently contribute to rational drug development, an important component of the NCI's initiative to incorporate state-of-the-art cancer treatments into clinical practice.